Each year approximately 1 in 1,000 pregnant women will experience peripartum cardiomyopathy, an uncommon form of often severe heart failure that occurs in the final month of pregnancy or up to five months following delivery. But the cause of peripartum cardiomyopathy has been largely unknown – until now. Researchers from the Perelman School of Medicine at the University of Pennsylvania analysed the genetic variants that have been associated with another form of inherited cardiomyopathy, and determined that peripartum cardiomyopathy is often the result of a genetic mutation.
Researchers analysed 43 genes in 172 women who experienced peripartum cardiomyopathy, and found that 15 percent of the group had genetic mutations, usually in their TTN gene, which encodes the instructions for making the Titin protein. This protein—named after the Greek gods, Titans—is the largest protein in the body and directly affects the heart’s ability to contract and relax. Of the women analysed, 26 were identified to have mutations on the TTN gene, an effect that is significantly higher than any other reported finding for the cause of peripartum cardiomyopathy.
“Until now, we had very little insight into the cause of peripartum cardiomyopathy,” said the study’s senior author, Zoltan Arany, MD, PhD, an associate professor of Cardiovascular Medicine. “There had been theories that it was linked to a viral infection, or paternal genes attacking the mother’s circulatory system, or just the stresses of pregnancy. However, this research shows that a mutation in the TTN gene is the cause of a significant number of peripartum cardiomyopathies, even in women without a family history of the disease.”
This sizable percentage indicates that peripartum cardiomyopathy is caused by genetic mutations. The same mutations are also present in many who experienced dilated cardiomyopathy, a condition in which the heart’s ability to pump blood is decreased when the main pumping chamber becomes weak and enlarged. This is similar to peripartum cardiomyopathy but most often occurs in older patients. However, the two diseases are not the same. For example, a woman with the genetic mutation for dilated cardiomyopathy will not always experience peripartum cardiomyopathy, and women with the peripartum cardiomyopathy mutation will not always experience dilated cardiomyopathy later in life. How the same mutations can lead to different conditions in different people remains an unanswered question.
Arany added, “these findings will certainly inform future peripartum cardiomyopathy research, with possible implications on genetic testing and preventive care. Though, more research is unquestionably needed. We’re continuing to follow these women and we’re gathering data for hundreds of others around the world, with the goal of identifying the cause of peripartum cardiomyopathy in the remaining 85 percent of women with this condition, and ultimately using what we learn to improve the care of these women and their newborns.”
Penn Medicine News
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The presence or absence of the CAP2 gene causes sudden cardiac death in mice, according to new research from the Perelman School of Medicine at the University of Pennsylvania. In particular, the absence of the gene interrupts the animal’s ability to send electrical signals to the heart to tell it to contract, a condition called cardiac conduction disease.
“This study proves that the CAP2 gene is directly responsible for cardiac conduction disease in mice,” said senior author Jeffrey Field, PhD, a professor of Systems Pharmacology and Translational Therapeutics. Heart disease is the leading cause of death among men in the United States. There are several risk factors for heart disease, many of which can be controlled with changes in behaviours and medication, but there are also hard-wired genetic factors that play a role. “Since humans have the same CAP2 gene, what we learn from the mice could advance our understanding of heart disease.”
Researchers have known that the CAP2 gene could be implicated in heart disease. However, its effect on cardiac conduction in the mouse heart was a surprise, Field said. The cardiac conduction system is a molecular network that sends electrical signals to the heart, telling it to contract in the correct rhythm to keep blood flowing smoothly.
The CAP2 gene’s class of protein, while known to regulate the structure or cytoskeleton of the heart, is not usually associated with cardiac conduction because this function is governed by a different family of proteins associated with cell communication. “Initially, saying that CAP2 is involved in cardiac conduction is like saying a person with a broken bone isn’t able to talk,” Field said. “The bone’s structural function and the ability to talk are each from entirely different systems. There’s no relationship. This finding merits further study to see how exactly CAP2 regulates conduction. While we don’t understand how, this gene definitely has a role in controlling conduction.”
Using a mouse model in which the team deleted the CAP2 gene, they found that most newborn males died suddenly, soon after weaning. The males were also prone to eye infections, and their eyes developed incorrectly and could not efficiently flush away debris. The knockout mice were also smaller in overall body size.
Though rare, some of the mice also developed hearts that were overly large. “The loss of the CAP2 gene resulted in bigger hearts because the heart had trouble contracting and to compensate, it dilated in order to get more blood flowing,” Field said.
The knockout mice also exhibited arrhythmia that worsened over four to five days. “We were able to monitor the mice as they died. Their hearts beat slower and slower, and they quickly died of heart block,” he said. Heart block happens when the heart atriums contract, but the ventricles do not get the signal to contract. As a result, the mouse hearts missed a few beats at first, and then stopped completely. This condition is called sudden cardiac death, which is distinct from a heart attack caused by clogged arteries impeding blood supply to the heart. In this experiment, there were no observable effects of a missing CAP2 gene on the female newborns.
Studies of some children with a rare developmental problem, called 6p22 syndrome, hint that this gene is associated with similar cardiac issues in people. These children have deep-set eyes and cardiac problems that are not well defined. “Almost all of these children are born with a deletion of one of their copies of the CAP2 gene,” Field noted.
Knowing this connection, the researchers generated mice that would exhibit only cardiac conduction disease (CCD). They reinstated the gene but this time engineered it so they could knock it out again, but this time only in the hearts of the mice. “It took close to five years to perfect this mouse model that exhibited only the heart knockout,” Field said. The researchers could then conduct experiments targeting only the heart problem, because all the other symptoms, such as the eye problems, were out of the picture.
The mice once again developed CCD, leading to sudden cardiac death from complete heart block, but there was an extra surprise this time. The female newborns also died of CCD. “That’s a puzzle for us. We’d be interested in studying why the gender specificity for CAP2-related sudden cardiac death goes away when we knock the gene out just in the heart,” Field said.
The team says that the study increases the understanding of how the CAP2 gene affects heart disease, but it also raises new questions that underline the need for further research heart disease and why it’s a major cause of death in humans.
Perelman School of Medicine
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Chemicals used as flame retardants that are potentially harmful to humans are found in hair, toenails and fingernails, according to new research from Indiana University.
The discovery of an easily available biomarker should ease the way for further research to determine the human impact of chemicals commonly found in the environment, including in indoor dust, water and air.
Exposure to flame retardants in various forms has been linked to obesity, learning disabilities, neuro and reproductive toxicity, and endocrine disruption. Flame retardants are frequently added to plastic, foam, wood and textiles. They are used in both commercial and consumer products worldwide to delay ignition and to slow the spread of fire. Flame retardants persist in the environment and bio-accumulate in ecosystems and in human tissues.
“Little is known about the human exposure to flame retardants, especially new classes of the retardants,” said researcher Amina Salamova at the School of Public and Environmental Affairs at IU Bloomington. “The first step is to establish a relatively easy and reliable way of measuring chemical levels in people, especially children, and we’ve determined that hair and nails can provide exactly that.”
Until now, researchers depended on samples of human milk, blood and urine, and those samples are more difficult to obtain than hair and nails.
The researchers collected hair, fingernails and toenails from 50 students in Bloomington and compared the levels of chemicals found in those samples with what was found in blood from the same people.
Salamova and colleagues found that there was a strong relationship between the levels of a large group of flame retardants, the polybrominated diphenyl ethers or PBDEs, in hair and nails, on the one hand, and those in serum, on the other. In some cases, women had higher concentrations of common flame retardants, and the researchers speculate that was a result of nail polishes that contain these chemicals.
Indiana University
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Researchers seeking to better understand how our genes contribute to stroke risk have completed what is believed to be the largest and most comprehensive review of the human genome to identify genes that predispose people to ischemic stroke, the cause of approximately 85 percent of all stroke cases.
The research has confirmed the role of the handful of genes previously suspected, ruled out others and identified a new gene that may become a drug target for doctors seeking to prevent this potentially deadly and often debilitating condition.
Stroke is the No. 2 killer worldwide, and risk factors such as smoking, high blood pressure, diabetes and high cholesterol are well established. Our genes, however, also play an important role in determining our stroke risk, but relatively little is known about the inheritable risk for ischemic stroke. (Ischemic strokes are caused by blood clots, while other forms of stroke are caused by the rupturing of blood vessels.)
To advance the understanding of ischemic stroke, a massive study has been conducted by researchers with the National Institute of Neurological Disorders and Stroke’s Stroke Genetics Network (SiGN) and the International Stroke Genetics Consortium (ISGC). The project is believed to be roughly twice as large as any previous study investigating the genetic factors contributing to ischemic stroke. The project examined the genomes of tens of thousands of stroke patients and far more control subjects. It represents the work of researchers around the world, including doctors and scientists at the University of Virginia Health System.
“We have started to alter the mortality from stroke, which is great and exciting,” said Bradford Worrall, MD, a top stroke expert at UVA and a leader of the project. “However, if you look at all the known risk factors, they are fairly poor at predicting an individual’s risk. There’s some statistics that suggest as much as 50 percent of the residual risk is unexplained, which is why understanding the underlying genetic contributors is so important.”
University of Virginia Health System
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IRB Barcelona has identified GEMC1 as a master gene for the generation of multiciliated cells—cells with fine filaments that move fluids and substances—which are found exclusively in the brain, respiratory tract, and reproductive system.
Defects in multiciliated cells lead to ciliopathies—rare and complex diseases that are poorly understood and for which not all causative genes have been identified.
The genomic sequencing of hundreds of patients with diverse types of ciliopathies has revealed that “in many cases the gene responsible is not known”, says Travis Stracker, head of the Genomic Instability and Cancer Lab at the IRB Barcelona. “So many people do not have a molecular diagnosis,” stresses the researcher. “Our work seeks to contribute to bridging this knowledge gap”.
A study on mice by Travis Stracker and his team, in collaboration with Vincenzo Costanzo’s laboratory at the FIRC Institute of Molecular Oncology (IFOM) in Milan, in which they reveal a gene candidate for a subtype of human ciliopathy. The gene in question, GEMC1, is indispensable for the generation of multiciliated cells specific to tissues such as the brain, trachea, lungs and oviducts.
The surface of multiciliated cells is covered by hundreds of cilia. These tiny, hairlike structures serve to circulate cerebrospinal fluid, remove mucus from the respiratory tract, and transport ovum through the oviduct, among other functions. Defects in the generation or function of these cells causes a subtype of ciliopathies called Mucociliary Clearance Disorders.
Specifically, GEMC1-deficient mice produced by Stracker reproduce the symptoms of a rare disease called RGMC (Reduced Generation of Multiple Motile Cilia)—a condition that causes hydrocephaly, severe respiratory infections, and infertility. The work, led by IRB Barcelona PhD student Berta Terré and IFOM postdoctoral researcher Gabriele Piergiovanni, reports that GEMC1 regulates the only two genes known to date that underlie this disease, Multicilin and Cyclin O, thus making it a potential candidate gene for RGMC.
In addition, the study has revealed that GEMC1 is one of the most important genes in the gene signalling cascade for the production of multiciliated cells. This means that this gene affects many others that depend on its expression. The gene expression analysis of this first study has revealed at least 10 new candidate genes related to cilia, as well as dozens that were already known or suspected of being involved in the function of cilia.
IRB Barcelona
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Genetic errors identified in a new study led by Washington University School of Medicine in St. Louis may reduce risk of heart attacks and serve as a basis for developing new drugs designed to prevent heart disease.
To reduce risk of heart attack, the benefits of a healthy lifestyle are clear. But genetics can still stack the deck. Some people’s genes bestow a natural advantage — or disadvantage — in protecting against heart disease, the leading cause of death worldwide.
Now, a new study that included genetic data from more than 190,000 people has identified two genes that, when altered in specific ways, either promote or undermine cardiovascular health. The findings may help guide efforts to design new preventive drugs, similar to the way statins now are prescribed to lower “bad” cholesterol to reduce the risk of heart disease.
The research is from Washington University School of Medicine in St. Louis, the Broad Institute at Massachusetts Institute of Technology and Harvard.
“We identified genetic variation in several genes that associated with protection from coronary heart disease,” said first author Nathan O. Stitziel, MD, PhD, a Washington University cardiologist and assistant professor of medicine and genetics. “Our findings support the idea that therapies focused on a major pathway regulating triglycerides should help prevent the buildup of plaque in the heart’s coronary arteries and protect against heart attacks.”
To identify genes that might be relevant for drug discovery, the investigators plumbed DNA data from patients with coronary disease and from healthy controls. They searched across more than 220,000 genetic variants that altered proteins to identify those that appeared to influence heart disease risk. Errors in proteins can have major physiologic consequences.
As part of the study, the researchers confirmed past work identifying genes already shown to confer an advantage or a vulnerability in protecting against heart disease risk, and they implicated two new ones — ANGPTL4 and SVEP1. Rare errors in ANGPTL4 were associated with reduced risk of coronary artery disease. The reduction varied from 14 percent for a small error in the gene to cutting risk by about 50 percent when an entire copy of the gene was disabled. The other gene, SVEP1, showed the opposite correlation — a rare error increased risk of coronary artery disease by about 14 percent.
While ANGPTL4 has been the subject of much study, the other gene newly implicated in cardiovascular health is a bit of a mystery. In the new study, Stitziel and his colleagues showed that the error in SVEP1 also was linked to higher blood pressure in their study populations, but beyond that there are few clues to what it’s doing.
In contrast, ANGPTL4 has long been known to play a role in processing triglycerides, a type of fat that circulates in the bloodstream. Doctors measure levels of triglycerides as a marker of heart disease risk, though whether these fats play a role in causing plaque to build up in arteries historically has been a matter of debate. ANGPTL4’s role in processing triglycerides is part of a system called the lipoprotein lipase (LPL) pathway. Blocking ANGPTL4 actually opens up this pathway, allowing the body to process triglycerides from the diet and get them out of the bloodstream.
“The gene’s association with lower triglycerides has been known for a while,” said Stitziel, who also sees patients at Barnes-Jewish Hospital. “But for a long time it was not clear that high triglycerides were a cause of coronary disease rather than a marker of it. Now we know that errors in ANGPTL4 associate with both reduced triglycerides and lower risk of coronary disease. This is another piece of the puzzle that points to a causal role for triglycerides in coronary disease.”
Washington University School of Medicine in St. Louis
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Male breast cancer (MBC) is a very rare tumour type, occurring in just 1% of all breast cancer cases, and the underlying genetic causes and treatment of MBC is not well understood. In a paper, researchers from Italy and the U.S. describe novel genetic variants found in a hormone receptor positive (HR+) MBC patient, that are distinct from previously identified genetic variants found in ten MBC cases.
The authors present the treatment history of a HR+ male breast cancer patient. His disease stabilized from targeting of the PI3K/mTOR pathway using the PI3K/mTOR inhibitor BEZ235 in combination with everolimus as 3rd line treatment for his metastatic ductal carcinoma and experienced a prolonged stable disease. After 18 months he subsequently became resistant to the treatment and his disease progressed. The authors then investigated why the patient benefited and subsequently developed resistance to this combination treatment using genomic and immunohistochemical analysis.
Whole-exome sequencing was performed on pre-treatment and post-progression samples of the MBC patient, as compared to a whole blood normal control. The researchers found that a region of Chromosome 12p was deleted in the resistant tumour and that HR protein expression was increased in the resistant tumour. This research provides new insights into both male breast cancer and response to BEZ235/everolimus combination treatment. This study adds to our understanding of MBC development and resistance, and the authors commented that ”Breast cancer in men is a very rare disease, representing less than 1% of all breast cancer cases. So, very few and small studies have been conducted in this disease. Our analyses contributed to delineate the genomic landscape of male breast cancer and suggested a potential particular benefit in this disease by the combined treatment with Afinitor plus BEZ235 in order to achieve a complete blockade of the PI3K/Akt/mTOR pathway.
University of Verona
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A blood test may be able to sound early warning bells that patients with advanced melanoma skin cancer are relapsing, according to a study.
Scientists from the Cancer Research UK Manchester Institute studied the DNA shed by tumours into the bloodstream – called circulating tumour DNA – in blood samples from seven advanced melanoma patients at The Christie NHS Foundation Trust.
“Being able to track cancers in real time as they evolve following treatment has huge potential for the way we monitor cancers and intervene to stop them growing back.’ – Professor Peter Johnson, Cancer Research UK’s chief clinician
In this early work they found they could see whether a patient was relapsing by tracking levels of circulating tumour DNA. And they found that new mutations in genes like NRAS and PI3K appeared, possibly causing the relapse by allowing the tumour to become resistant to treatment.
Most melanoma patients respond to treatment at first but their cancer can become resistant within a year. It is hoped that these approaches will allow doctors to use circulating tumour DNA to tailor treatment for individual patients to get the best result.
Around 40 to 50 per cent of melanoma patients have a faulty BRAF gene and they can be treated with the targeted drugs vemurafenib or dabrafenib. But for many of these patients the treatments don’t work, or their tumours develop resistance after a relatively short time. When this happens these patients can be offered immunotherapy drugs including pembrolizumab, nivolumab and ipilimumab. Detecting this situation early could be key to improving their care and chances of survival.
Cancer Research UK Manchester Institute
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ELISA and indirect immunofluorescence tests (IIFT) have been developed for sensitive and specific detection of antibodies against Zika virus in patient serum samples. The assays are suitable for diagnosing acute infections as well as for disease surveillance. In particular, serological analyses can aid the differentiation of infections with Zika virus, dengue virus and chikungunya virus, which manifest with similar symptoms and are endemic in much the same geographic regions. Anti-Zika Virus ELISA (IgM or IgG) are based on highly specific recombinant Zika NS1 protein which avoids cross reactivity with other flaviviruses. Data from panels of well characterized sera have confirmed that there is no cross reactivity with flaviviruses including dengue, West Nile, yellow fever and Japanese encephalitis viruses. In studies on clinically and serologically characterized samples the IgM and IgG ELISA showed 100% sensitivity and 100% specificity. Anti-Zika Virus IIFT (IgM or IgG) utilize Zika virus-infected cells as the antigenic substrate. Positive and negative results are evaluated by fluorescence microscopy. With the Arboviral Fever Mosaic 2 the Zika virus substrate is incubated in parallel with substrates for chikungunya virus and dengue virus serotypes 1 to 4. This BIOCHIP combination can help in the differential diagnosis of Zika, dengue and chikungunya virus infections. Due to the use of whole virus particles, cross reactivities between flavivirus antibodies can occur. Serological tests provide a longer window for diagnosis than direct detection methods, which are only effective during the viremic phase within the first week after onset of symptoms. Detection of specific IgM or a significant rise in specific IgG in a pair of samples taken seven to ten days apart is evidence of an acute infection. Serological analyses are also important for prenatal monitoring, screening of donated blood and epidemiological studies. Zika virus is the pathogenic agent of Zika fever, an infectious topical disease which manifests with fever, exanthema and arthritis. Zika virus infection has been linked to congenital malformations, in particular microcephaly, and neurological complications such as Guillain-Barré syndrome. The virus is transmitted by mosquitoes of the Aedes family. Zika virus is currently spreading explosively in the Americas.
Euroimmunwww.euroimmun.de
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Scientists at the University of Warwick have discovered that a lack of stem cells in the womb lining is causing thousands of women to suffer from recurrent miscarriages.
The academics behind the breakthrough are now to start research into a treatment which they believe could bring hope to those who have suffered failed pregnancies.
Professor Jan Brosens, Professor of Obstetrics & Gynaecology at Warwick Medical School at the University of Warwick, and Consultant in Reproductive Health atUniversity Hospitals Coventry and Warwickshire NHS Trust , led the team who unearthed the link between stem cells and miscarriage. He said: “We have discovered that the lining of the womb in the recurrent miscarriage patients we studied is already defective before pregnancy.
“I can envisage that we will be able to correct these defects before the patient tries to achieve another pregnancy. In fact, this may be the only way to really prevent miscarriages in these cases.”
The team found a shortfall of stem cells is the likely cause of accelerated ageing of the lining of the womb which results in the failure of some pregnancies.
Miscarriage is the most common cause of loss; between 15-25% of pregnancies end in miscarriage and one in 100 women trying to conceive suffer recurrent miscarriages, defined as the loss of three or more consecutive pregnancies.
The researchers examined tissue samples from the womb lining, donated by 183 women who were being treated at the Implantation Research Clinic, University Hospitals Coventry and Warwickshire NHS Trust.
The team found that an epigenetic signature – which is typical of stem cells – was absent in cultures established from womb biopsies taken from women suffering recurrent miscarriages. Indeed, fewer stem cells could be isolated from the lining of the womb from recurrent miscarriage patients when compared to women in the study’s control group.
The researchers further found that a stem cell shortage accelerates cellular ageing in the womb. The lining has to renew itself each cycle, each miscarriage and successful birth. This renewal capacity is dependent on resident stem cell population. A shortage of these stem cells in patients suffering recurrent loss is associated with accelerated ageing of the tissue. Ageing cells mount an inflammatory response, which may facilitate implantation of an embryo but is detrimental for its further development.
Professor Brosens added: “After an embryo has implanted, the lining of the uterus develops into a specialised structure called the decidua, and this process can be replicated when cells from the uterus are cultured in the lab.
“Cultured cells from women who had had three or more consecutive miscarriages showed that ageing cells in the lining of the womb don’t have the ability to prepare adequately for pregnancy.”
University of Warwick
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Cause of heart failure in pregnant women
, /in E-News /by 3wmediaEach year approximately 1 in 1,000 pregnant women will experience peripartum cardiomyopathy, an uncommon form of often severe heart failure that occurs in the final month of pregnancy or up to five months following delivery. But the cause of peripartum cardiomyopathy has been largely unknown – until now. Researchers from the Perelman School of Medicine at the University of Pennsylvania analysed the genetic variants that have been associated with another form of inherited cardiomyopathy, and determined that peripartum cardiomyopathy is often the result of a genetic mutation.
Researchers analysed 43 genes in 172 women who experienced peripartum cardiomyopathy, and found that 15 percent of the group had genetic mutations, usually in their TTN gene, which encodes the instructions for making the Titin protein. This protein—named after the Greek gods, Titans—is the largest protein in the body and directly affects the heart’s ability to contract and relax. Of the women analysed, 26 were identified to have mutations on the TTN gene, an effect that is significantly higher than any other reported finding for the cause of peripartum cardiomyopathy.
“Until now, we had very little insight into the cause of peripartum cardiomyopathy,” said the study’s senior author, Zoltan Arany, MD, PhD, an associate professor of Cardiovascular Medicine. “There had been theories that it was linked to a viral infection, or paternal genes attacking the mother’s circulatory system, or just the stresses of pregnancy. However, this research shows that a mutation in the TTN gene is the cause of a significant number of peripartum cardiomyopathies, even in women without a family history of the disease.”
This sizable percentage indicates that peripartum cardiomyopathy is caused by genetic mutations. The same mutations are also present in many who experienced dilated cardiomyopathy, a condition in which the heart’s ability to pump blood is decreased when the main pumping chamber becomes weak and enlarged. This is similar to peripartum cardiomyopathy but most often occurs in older patients. However, the two diseases are not the same. For example, a woman with the genetic mutation for dilated cardiomyopathy will not always experience peripartum cardiomyopathy, and women with the peripartum cardiomyopathy mutation will not always experience dilated cardiomyopathy later in life. How the same mutations can lead to different conditions in different people remains an unanswered question.
Arany added, “these findings will certainly inform future peripartum cardiomyopathy research, with possible implications on genetic testing and preventive care. Though, more research is unquestionably needed. We’re continuing to follow these women and we’re gathering data for hundreds of others around the world, with the goal of identifying the cause of peripartum cardiomyopathy in the remaining 85 percent of women with this condition, and ultimately using what we learn to improve the care of these women and their newborns.” Penn Medicine News
Heart structural gene causes sudden cardiac death in animal model
, /in E-News /by 3wmediaThe presence or absence of the CAP2 gene causes sudden cardiac death in mice, according to new research from the Perelman School of Medicine at the University of Pennsylvania. In particular, the absence of the gene interrupts the animal’s ability to send electrical signals to the heart to tell it to contract, a condition called cardiac conduction disease.
“This study proves that the CAP2 gene is directly responsible for cardiac conduction disease in mice,” said senior author Jeffrey Field, PhD, a professor of Systems Pharmacology and Translational Therapeutics. Heart disease is the leading cause of death among men in the United States. There are several risk factors for heart disease, many of which can be controlled with changes in behaviours and medication, but there are also hard-wired genetic factors that play a role. “Since humans have the same CAP2 gene, what we learn from the mice could advance our understanding of heart disease.”
Researchers have known that the CAP2 gene could be implicated in heart disease. However, its effect on cardiac conduction in the mouse heart was a surprise, Field said. The cardiac conduction system is a molecular network that sends electrical signals to the heart, telling it to contract in the correct rhythm to keep blood flowing smoothly.
The CAP2 gene’s class of protein, while known to regulate the structure or cytoskeleton of the heart, is not usually associated with cardiac conduction because this function is governed by a different family of proteins associated with cell communication. “Initially, saying that CAP2 is involved in cardiac conduction is like saying a person with a broken bone isn’t able to talk,” Field said. “The bone’s structural function and the ability to talk are each from entirely different systems. There’s no relationship. This finding merits further study to see how exactly CAP2 regulates conduction. While we don’t understand how, this gene definitely has a role in controlling conduction.”
Using a mouse model in which the team deleted the CAP2 gene, they found that most newborn males died suddenly, soon after weaning. The males were also prone to eye infections, and their eyes developed incorrectly and could not efficiently flush away debris. The knockout mice were also smaller in overall body size.
Though rare, some of the mice also developed hearts that were overly large. “The loss of the CAP2 gene resulted in bigger hearts because the heart had trouble contracting and to compensate, it dilated in order to get more blood flowing,” Field said.
The knockout mice also exhibited arrhythmia that worsened over four to five days. “We were able to monitor the mice as they died. Their hearts beat slower and slower, and they quickly died of heart block,” he said. Heart block happens when the heart atriums contract, but the ventricles do not get the signal to contract. As a result, the mouse hearts missed a few beats at first, and then stopped completely. This condition is called sudden cardiac death, which is distinct from a heart attack caused by clogged arteries impeding blood supply to the heart. In this experiment, there were no observable effects of a missing CAP2 gene on the female newborns.
Studies of some children with a rare developmental problem, called 6p22 syndrome, hint that this gene is associated with similar cardiac issues in people. These children have deep-set eyes and cardiac problems that are not well defined. “Almost all of these children are born with a deletion of one of their copies of the CAP2 gene,” Field noted.
Knowing this connection, the researchers generated mice that would exhibit only cardiac conduction disease (CCD). They reinstated the gene but this time engineered it so they could knock it out again, but this time only in the hearts of the mice. “It took close to five years to perfect this mouse model that exhibited only the heart knockout,” Field said. The researchers could then conduct experiments targeting only the heart problem, because all the other symptoms, such as the eye problems, were out of the picture.
The mice once again developed CCD, leading to sudden cardiac death from complete heart block, but there was an extra surprise this time. The female newborns also died of CCD. “That’s a puzzle for us. We’d be interested in studying why the gender specificity for CAP2-related sudden cardiac death goes away when we knock the gene out just in the heart,” Field said.
The team says that the study increases the understanding of how the CAP2 gene affects heart disease, but it also raises new questions that underline the need for further research heart disease and why it’s a major cause of death in humans. Perelman School of Medicine
Human hair and nails can tell toxic secrets
, /in E-News /by 3wmediaChemicals used as flame retardants that are potentially harmful to humans are found in hair, toenails and fingernails, according to new research from Indiana University.
The discovery of an easily available biomarker should ease the way for further research to determine the human impact of chemicals commonly found in the environment, including in indoor dust, water and air.
Exposure to flame retardants in various forms has been linked to obesity, learning disabilities, neuro and reproductive toxicity, and endocrine disruption. Flame retardants are frequently added to plastic, foam, wood and textiles. They are used in both commercial and consumer products worldwide to delay ignition and to slow the spread of fire. Flame retardants persist in the environment and bio-accumulate in ecosystems and in human tissues.
“Little is known about the human exposure to flame retardants, especially new classes of the retardants,” said researcher Amina Salamova at the School of Public and Environmental Affairs at IU Bloomington. “The first step is to establish a relatively easy and reliable way of measuring chemical levels in people, especially children, and we’ve determined that hair and nails can provide exactly that.”
Until now, researchers depended on samples of human milk, blood and urine, and those samples are more difficult to obtain than hair and nails.
The researchers collected hair, fingernails and toenails from 50 students in Bloomington and compared the levels of chemicals found in those samples with what was found in blood from the same people.
Salamova and colleagues found that there was a strong relationship between the levels of a large group of flame retardants, the polybrominated diphenyl ethers or PBDEs, in hair and nails, on the one hand, and those in serum, on the other. In some cases, women had higher concentrations of common flame retardants, and the researchers speculate that was a result of nail polishes that contain these chemicals. Indiana University
Review of human genome IDs stroke risk genes
, /in E-News /by 3wmediaResearchers seeking to better understand how our genes contribute to stroke risk have completed what is believed to be the largest and most comprehensive review of the human genome to identify genes that predispose people to ischemic stroke, the cause of approximately 85 percent of all stroke cases.
The research has confirmed the role of the handful of genes previously suspected, ruled out others and identified a new gene that may become a drug target for doctors seeking to prevent this potentially deadly and often debilitating condition.
Stroke is the No. 2 killer worldwide, and risk factors such as smoking, high blood pressure, diabetes and high cholesterol are well established. Our genes, however, also play an important role in determining our stroke risk, but relatively little is known about the inheritable risk for ischemic stroke. (Ischemic strokes are caused by blood clots, while other forms of stroke are caused by the rupturing of blood vessels.)
To advance the understanding of ischemic stroke, a massive study has been conducted by researchers with the National Institute of Neurological Disorders and Stroke’s Stroke Genetics Network (SiGN) and the International Stroke Genetics Consortium (ISGC). The project is believed to be roughly twice as large as any previous study investigating the genetic factors contributing to ischemic stroke. The project examined the genomes of tens of thousands of stroke patients and far more control subjects. It represents the work of researchers around the world, including doctors and scientists at the University of Virginia Health System.
“We have started to alter the mortality from stroke, which is great and exciting,” said Bradford Worrall, MD, a top stroke expert at UVA and a leader of the project. “However, if you look at all the known risk factors, they are fairly poor at predicting an individual’s risk. There’s some statistics that suggest as much as 50 percent of the residual risk is unexplained, which is why understanding the underlying genetic contributors is so important.” University of Virginia Health System
Gene associated with a set of poorly understood rare diseases
, /in E-News /by 3wmediaIRB Barcelona has identified GEMC1 as a master gene for the generation of multiciliated cells—cells with fine filaments that move fluids and substances—which are found exclusively in the brain, respiratory tract, and reproductive system.
Defects in multiciliated cells lead to ciliopathies—rare and complex diseases that are poorly understood and for which not all causative genes have been identified.
The genomic sequencing of hundreds of patients with diverse types of ciliopathies has revealed that “in many cases the gene responsible is not known”, says Travis Stracker, head of the Genomic Instability and Cancer Lab at the IRB Barcelona. “So many people do not have a molecular diagnosis,” stresses the researcher. “Our work seeks to contribute to bridging this knowledge gap”.
A study on mice by Travis Stracker and his team, in collaboration with Vincenzo Costanzo’s laboratory at the FIRC Institute of Molecular Oncology (IFOM) in Milan, in which they reveal a gene candidate for a subtype of human ciliopathy. The gene in question, GEMC1, is indispensable for the generation of multiciliated cells specific to tissues such as the brain, trachea, lungs and oviducts.
The surface of multiciliated cells is covered by hundreds of cilia. These tiny, hairlike structures serve to circulate cerebrospinal fluid, remove mucus from the respiratory tract, and transport ovum through the oviduct, among other functions. Defects in the generation or function of these cells causes a subtype of ciliopathies called Mucociliary Clearance Disorders.
Specifically, GEMC1-deficient mice produced by Stracker reproduce the symptoms of a rare disease called RGMC (Reduced Generation of Multiple Motile Cilia)—a condition that causes hydrocephaly, severe respiratory infections, and infertility. The work, led by IRB Barcelona PhD student Berta Terré and IFOM postdoctoral researcher Gabriele Piergiovanni, reports that GEMC1 regulates the only two genes known to date that underlie this disease, Multicilin and Cyclin O, thus making it a potential candidate gene for RGMC.
In addition, the study has revealed that GEMC1 is one of the most important genes in the gene signalling cascade for the production of multiciliated cells. This means that this gene affects many others that depend on its expression. The gene expression analysis of this first study has revealed at least 10 new candidate genes related to cilia, as well as dozens that were already known or suspected of being involved in the function of cilia. IRB Barcelona
Genetic errors may prevent heart attacks
, /in E-News /by 3wmediaGenetic errors identified in a new study led by Washington University School of Medicine in St. Louis may reduce risk of heart attacks and serve as a basis for developing new drugs designed to prevent heart disease.
To reduce risk of heart attack, the benefits of a healthy lifestyle are clear. But genetics can still stack the deck. Some people’s genes bestow a natural advantage — or disadvantage — in protecting against heart disease, the leading cause of death worldwide.
Now, a new study that included genetic data from more than 190,000 people has identified two genes that, when altered in specific ways, either promote or undermine cardiovascular health. The findings may help guide efforts to design new preventive drugs, similar to the way statins now are prescribed to lower “bad” cholesterol to reduce the risk of heart disease.
The research is from Washington University School of Medicine in St. Louis, the Broad Institute at Massachusetts Institute of Technology and Harvard.
“We identified genetic variation in several genes that associated with protection from coronary heart disease,” said first author Nathan O. Stitziel, MD, PhD, a Washington University cardiologist and assistant professor of medicine and genetics. “Our findings support the idea that therapies focused on a major pathway regulating triglycerides should help prevent the buildup of plaque in the heart’s coronary arteries and protect against heart attacks.”
To identify genes that might be relevant for drug discovery, the investigators plumbed DNA data from patients with coronary disease and from healthy controls. They searched across more than 220,000 genetic variants that altered proteins to identify those that appeared to influence heart disease risk. Errors in proteins can have major physiologic consequences.
As part of the study, the researchers confirmed past work identifying genes already shown to confer an advantage or a vulnerability in protecting against heart disease risk, and they implicated two new ones — ANGPTL4 and SVEP1. Rare errors in ANGPTL4 were associated with reduced risk of coronary artery disease. The reduction varied from 14 percent for a small error in the gene to cutting risk by about 50 percent when an entire copy of the gene was disabled. The other gene, SVEP1, showed the opposite correlation — a rare error increased risk of coronary artery disease by about 14 percent.
While ANGPTL4 has been the subject of much study, the other gene newly implicated in cardiovascular health is a bit of a mystery. In the new study, Stitziel and his colleagues showed that the error in SVEP1 also was linked to higher blood pressure in their study populations, but beyond that there are few clues to what it’s doing.
In contrast, ANGPTL4 has long been known to play a role in processing triglycerides, a type of fat that circulates in the bloodstream. Doctors measure levels of triglycerides as a marker of heart disease risk, though whether these fats play a role in causing plaque to build up in arteries historically has been a matter of debate. ANGPTL4’s role in processing triglycerides is part of a system called the lipoprotein lipase (LPL) pathway. Blocking ANGPTL4 actually opens up this pathway, allowing the body to process triglycerides from the diet and get them out of the bloodstream.
“The gene’s association with lower triglycerides has been known for a while,” said Stitziel, who also sees patients at Barnes-Jewish Hospital. “But for a long time it was not clear that high triglycerides were a cause of coronary disease rather than a marker of it. Now we know that errors in ANGPTL4 associate with both reduced triglycerides and lower risk of coronary disease. This is another piece of the puzzle that points to a causal role for triglycerides in coronary disease.” Washington University School of Medicine in St. Louis
Novel gene variants identified in male breast cancer
, /in E-News /by 3wmediaMale breast cancer (MBC) is a very rare tumour type, occurring in just 1% of all breast cancer cases, and the underlying genetic causes and treatment of MBC is not well understood. In a paper, researchers from Italy and the U.S. describe novel genetic variants found in a hormone receptor positive (HR+) MBC patient, that are distinct from previously identified genetic variants found in ten MBC cases.
The authors present the treatment history of a HR+ male breast cancer patient. His disease stabilized from targeting of the PI3K/mTOR pathway using the PI3K/mTOR inhibitor BEZ235 in combination with everolimus as 3rd line treatment for his metastatic ductal carcinoma and experienced a prolonged stable disease. After 18 months he subsequently became resistant to the treatment and his disease progressed. The authors then investigated why the patient benefited and subsequently developed resistance to this combination treatment using genomic and immunohistochemical analysis.
Whole-exome sequencing was performed on pre-treatment and post-progression samples of the MBC patient, as compared to a whole blood normal control. The researchers found that a region of Chromosome 12p was deleted in the resistant tumour and that HR protein expression was increased in the resistant tumour. This research provides new insights into both male breast cancer and response to BEZ235/everolimus combination treatment. This study adds to our understanding of MBC development and resistance, and the authors commented that ”Breast cancer in men is a very rare disease, representing less than 1% of all breast cancer cases. So, very few and small studies have been conducted in this disease. Our analyses contributed to delineate the genomic landscape of male breast cancer and suggested a potential particular benefit in this disease by the combined treatment with Afinitor plus BEZ235 in order to achieve a complete blockade of the PI3K/Akt/mTOR pathway. University of Verona
Blood test may give early warning of skin cancer relapse
, /in E-News /by 3wmediaA blood test may be able to sound early warning bells that patients with advanced melanoma skin cancer are relapsing, according to a study.
Scientists from the Cancer Research UK Manchester Institute studied the DNA shed by tumours into the bloodstream – called circulating tumour DNA – in blood samples from seven advanced melanoma patients at The Christie NHS Foundation Trust.
“Being able to track cancers in real time as they evolve following treatment has huge potential for the way we monitor cancers and intervene to stop them growing back.’ – Professor Peter Johnson, Cancer Research UK’s chief clinician
In this early work they found they could see whether a patient was relapsing by tracking levels of circulating tumour DNA. And they found that new mutations in genes like NRAS and PI3K appeared, possibly causing the relapse by allowing the tumour to become resistant to treatment.
Most melanoma patients respond to treatment at first but their cancer can become resistant within a year. It is hoped that these approaches will allow doctors to use circulating tumour DNA to tailor treatment for individual patients to get the best result.
Around 40 to 50 per cent of melanoma patients have a faulty BRAF gene and they can be treated with the targeted drugs vemurafenib or dabrafenib. But for many of these patients the treatments don’t work, or their tumours develop resistance after a relatively short time. When this happens these patients can be offered immunotherapy drugs including pembrolizumab, nivolumab and ipilimumab. Detecting this situation early could be key to improving their care and chances of survival. Cancer Research UK Manchester Institute
Specific serological tests for Zika virus
, /in E-News /by 3wmediaELISA and indirect immunofluorescence tests (IIFT) have been developed for sensitive and specific detection of antibodies against Zika virus in patient serum samples. The assays are suitable for diagnosing acute infections as well as for disease surveillance. In particular, serological analyses can aid the differentiation of infections with Zika virus, dengue virus and chikungunya virus, which manifest with similar symptoms and are endemic in much the same geographic regions. Anti-Zika Virus ELISA (IgM or IgG) are based on highly specific recombinant Zika NS1 protein which avoids cross reactivity with other flaviviruses. Data from panels of well characterized sera have confirmed that there is no cross reactivity with flaviviruses including dengue, West Nile, yellow fever and Japanese encephalitis viruses. In studies on clinically and serologically characterized samples the IgM and IgG ELISA showed 100% sensitivity and 100% specificity. Anti-Zika Virus IIFT (IgM or IgG) utilize Zika virus-infected cells as the antigenic substrate. Positive and negative results are evaluated by fluorescence microscopy. With the Arboviral Fever Mosaic 2 the Zika virus substrate is incubated in parallel with substrates for chikungunya virus and dengue virus serotypes 1 to 4. This BIOCHIP combination can help in the differential diagnosis of Zika, dengue and chikungunya virus infections. Due to the use of whole virus particles, cross reactivities between flavivirus antibodies can occur. Serological tests provide a longer window for diagnosis than direct detection methods, which are only effective during the viremic phase within the first week after onset of symptoms. Detection of specific IgM or a significant rise in specific IgG in a pair of samples taken seven to ten days apart is evidence of an acute infection. Serological analyses are also important for prenatal monitoring, screening of donated blood and epidemiological studies. Zika virus is the pathogenic agent of Zika fever, an infectious topical disease which manifests with fever, exanthema and arthritis. Zika virus infection has been linked to congenital malformations, in particular microcephaly, and neurological complications such as Guillain-Barré syndrome. The virus is transmitted by mosquitoes of the Aedes family. Zika virus is currently spreading explosively in the Americas.
Euroimmunwww.euroimmun.de
Lack of stem cells to blame for recurrent miscarriages
, /in E-News /by 3wmediaScientists at the University of Warwick have discovered that a lack of stem cells in the womb lining is causing thousands of women to suffer from recurrent miscarriages.
The academics behind the breakthrough are now to start research into a treatment which they believe could bring hope to those who have suffered failed pregnancies.
Professor Jan Brosens, Professor of Obstetrics & Gynaecology at Warwick Medical School at the University of Warwick, and Consultant in Reproductive Health atUniversity Hospitals Coventry and Warwickshire NHS Trust , led the team who unearthed the link between stem cells and miscarriage. He said: “We have discovered that the lining of the womb in the recurrent miscarriage patients we studied is already defective before pregnancy.
“I can envisage that we will be able to correct these defects before the patient tries to achieve another pregnancy. In fact, this may be the only way to really prevent miscarriages in these cases.”
The team found a shortfall of stem cells is the likely cause of accelerated ageing of the lining of the womb which results in the failure of some pregnancies.
Miscarriage is the most common cause of loss; between 15-25% of pregnancies end in miscarriage and one in 100 women trying to conceive suffer recurrent miscarriages, defined as the loss of three or more consecutive pregnancies.
The researchers examined tissue samples from the womb lining, donated by 183 women who were being treated at the Implantation Research Clinic, University Hospitals Coventry and Warwickshire NHS Trust.
The team found that an epigenetic signature – which is typical of stem cells – was absent in cultures established from womb biopsies taken from women suffering recurrent miscarriages. Indeed, fewer stem cells could be isolated from the lining of the womb from recurrent miscarriage patients when compared to women in the study’s control group.
The researchers further found that a stem cell shortage accelerates cellular ageing in the womb. The lining has to renew itself each cycle, each miscarriage and successful birth. This renewal capacity is dependent on resident stem cell population. A shortage of these stem cells in patients suffering recurrent loss is associated with accelerated ageing of the tissue. Ageing cells mount an inflammatory response, which may facilitate implantation of an embryo but is detrimental for its further development.
Professor Brosens added: “After an embryo has implanted, the lining of the uterus develops into a specialised structure called the decidua, and this process can be replicated when cells from the uterus are cultured in the lab.
“Cultured cells from women who had had three or more consecutive miscarriages showed that ageing cells in the lining of the womb don’t have the ability to prepare adequately for pregnancy.” University of Warwick